Definition of two agonist types at the mammalian cold-activated channel TRPM8
- University of Leuven, Belgium
Abstract
Various TRP channels act as polymodal sensors of thermal and chemical stimuli, but the mechanisms whereby chemical ligands impact on TRP channel gating are poorly understood. Here we show that AITC (allyl isothiocyanate; mustard oil) and menthol represent two distinct types of ligands at the mammalian cold sensor TRPM8. Kinetic analysis of channel gating revealed that AITC acts by destabilizing the closed channel, whereas menthol stabilizes the open channel, relative to the transition state. Based on these differences, we classify agonists as either type I (menthol-like) or type II (AITC-like), and provide a kinetic model that faithfully reproduces their differential effects. We further demonstrate that type I and type II agonists have a distinct impact on TRPM8 currents and TRPM8-mediated calcium signals in excitable cells. These findings provide a theoretical framework for understanding the differential actions of TRP channel ligands, with important ramifications for TRP channel structure-function analysis and pharmacology.
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Author details
Funding
Fonds Wetenschappelijk Onderzoek (G.0565.07)
- Thomas Voets
Onderzoeksraad, KU Leuven (PF-TRPLe)
- Rudi Vennekens
- Thomas Voets
Belspo (IUAP P7/13)
- Rudi Vennekens
- Karel Talavera
- Thomas Voets
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the KU Leuven Ethical Committee Laboratory Animals under project number P192/2014.
Copyright
© 2016, Annelies et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Definition of two agonist types at the mammalian cold-activated channel TRPM8
eLife 5:e17240.
https://doi.org/10.7554/eLife.17240
